ABSTRACT

Context Evidence suggests that early adverse experiences play a preeminent role
in development of mood and anxiety disorders and that corticotropin-releasing
factor (CRF) systems may mediate this association.

Objective To determine whether early-life stress results in a persistent sensitization
of the hypothalamic-pituitary-adrenal axis to mild stress in adulthood, thereby
contributing to vulnerability to psychopathological conditions.

Design and Setting Prospective controlled study conducted from May 1997 to July 1999 at
the General Clinical Research Center of Emory University Hospital, Atlanta,
Ga.

Participants Forty-nine healthy women aged 18 to 45 years with regular menses, with
no history of mania or psychosis, with no active substance abuse or eating
disorder within 6 months, and who were free of hormonal and psychotropic medications
were recruited into 4 study groups (n = 12 with no history of childhood abuse
or psychiatric disorder [controls]; n = 13 with diagnosis of current major
depression who were sexually or physically abused as children; n = 14 without
current major depression who were sexually or physically abused as children;
and n = 10 with diagnosis of current major depression and no history of childhood
abuse).

Conclusions Our findings suggest that hypothalamic-pituitary-adrenal axis and autonomic
nervous system hyperreactivity, presumably due to CRF hypersecretion, is a
persistent consequence of childhood abuse that may contribute to the diathesis
for adulthood psychopathological conditions. Furthermore, these results imply
a role for CRF receptor antagonists in the prevention and treatment of psychopathological
conditions related to early-life stress.

Figures in this Article

The relative contribution of genetic and environmental factors in the
etiology of psychiatric disorders has long been a hotly debated area of investigation.
Considerable evidence from a variety of studies suggests a preeminent role
of early adverse experiences in the development of mood and anxiety disorders.
One study1 composed of almost 2000 women revealed
that those with a history of childhood sexual or physical abuse exhibited
more symptoms of depression and anxiety and had more frequently attempted
suicide than women without a history of childhood abuse. Women who have been
abused in childhood are 4 times more likely to develop syndromal major depression
in adulthood than women who have not been abused, and the magnitude of the
abuse is correlated with the severity of depression.2

Early parental loss predominantly due to parental separation has also
been found to increase the risk for major depression in case-control and epidemiological
studies.3- 8
Twin studies9,10 have provided
concordant findings. Childhood abuse also predisposes to the development of
anxiety disorders in adulthood, including panic disorder and generalized anxiety
disorder.11,12 In addition, posttraumatic
stress disorder (PTSD) may be a direct consequence of childhood abuse, and,
moreover, such trauma early in life also appears to increase an individual's
risk of developing PTSD in response to other traumas in adulthood.13 Depression and anxiety disorders, including PTSD,
are often comorbid in individuals with a history of diverse early adversities.14

There is evidence that central nervous system (CNS) corticotropin-releasing
factor (CRF) systems are likely to mediate the association between early-life
stress and the development of mood and anxiety disorders in adulthood. Corticotropin-releasing
factor neurons are found not only in the hypothalamus, but also in the neocortex
and the central nucleus of the amygdala, which are believed to be involved
in cognitive and emotional processing and in brainstem nuclei that contain
the bulk of the noradrenergic and serotonergic perikarya that project to the
forebrain.

These CNS CRF systems have also been strongly implicated in the pathophysiology
of both depression and anxiety disorders.15
Thus, when administered directly into the CNS of laboratory animals, CRF produces
many physiological and behavioral changes that closely parallel symptoms of
depression and anxiety, such as elevations of peripheral adrenocorticotropic
hormone (ACTH), corticosterone, and catecholamine concentrations, increases
in heart rate and mean arterial pressure, changes in gastrointestinal activity,
decreased reproductive behavior, decreased appetite, disruption of sleep,
increased grooming behavior, increased locomotor activity in a familiar environment,
suppression of exploratory behavior in a novel environment, potentiation of
acoustic startle responses, facilitation of fear conditioning, and enhancement
of shock-induced freezing and fighting behavior.16- 20

Enhanced release of CRF from 1 or more CNS circuits may, thus, account
for many of the symptoms of depression and anxiety and for the frequent comorbidity
between these disorders.21,22
Indeed, our group and others have repeatedly measured increased CRF-like immunoreactivity
in cerebrospinal fluid (CSF) of untreated depressed patients compared with
healthy controls and patients with other psychiatric disorders.23- 26
Moreover, increased numbers of CRF-positive neurons and increased CRF messenger
RNA (mRNA) expression have recently been measured in the paraventricular nucleus
(PVN) in postmortem hypothalamic tissue of untreated depressed patients.27,28 Similar to findings in depression,
increased CSF CRF concentrations have been reported in patients with PTSD
and obsessive-compulsive disorder.29- 31

Of particular relevance to the current study is evidence from preclinical
studies that suggests that increased activity of CRF circuits may be the persisting
neurobiological consequence of stress early in development. Adult rats repeatedly
separated from their dams for 180 min/d on postnatal days 2 to 14 demonstrate
increased CRF concentrations in the median eminence, hypothalamohypophysial
portal blood, and CSF and increased CRF mRNA expression in the hypothalamic
PVN under resting conditions. In response to a variety of stressors, these
maternally separated rats exhibit increased CRF mRNA expression in the hypothalamic
PVN and increased ACTH and corticosterone responses.32,33
Similarly, nonhuman primates reared as neonates with their mothers in a variable
foraging demand condition for 12 weeks demonstrate significantly elevated
CSF CRF concentrations along with stable traits of anxiety as adults.34,35 We hypothesize that stress early
in life results in a persistent sensitization or hyperactivity of CNS CRF
systems to even mild stress in adulthood, contributing to the development
of mood and anxiety disorders. This study sought to test this hypothesis in
human subjects.

METHODS

Subjects

A total of 49 subjects, ages 18 to 45 years, distributed into 4 groups
participated in the study. Presuming a moderate effect size (10%) according
to Cohen,36 the power to detect a significant
interaction effect among 4 groups and a time series of 8 repeated measurements
at the .05 level of significance is 0.98.37

We recruited women without a history of significant early-life stress
and no psychiatric disorder (controls: n = 12; mean age, 29 years; 95% confidence
interval [CI], 24-34 years), women with a history of childhood sexual and/or
physical abuse (repeated abuse, once a month or more for at least 1 year;
sexual abuse, having been forced to touch another person's intimate parts,
having been touched in intimate parts, attempted or completed vaginal, oral,
or anal intercourse; physical abuse, having been spanked, kicked, or choked
in a way that left bruises or injuries, having been attacked with a weapon
or tied up or locked in a room or a closet; or both sexual and physical abuse,
before the first menstrual period) without a Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)38 diagnosis of current major
depression (n = 14; mean age, 30 years; 95% CI, 27-33 years), women with a
history of childhood sexual and/or physical abuse and a DSM-IV diagnosis of current major depression (n = 13; mean age, 32
years; 95% CI, 27-36 years), and women with a DSM-IV
diagnosis of current major depression but without a history of significant
early-life stress (n = 10; mean age, 34.6 years; 95% CI, 28.59-40.60 years).

All participants were recruited via newspaper advertising from the general
population and were remunerated for the time required for participation. Exclusion
criteria for the study were irregular menses, significant medical illness,
past or current presence of psychotic symptoms or bipolar disorder, and current
presence of substance abuse or dependency or eating disorders. All subjects
were free of hormonal (except for oral contraceptives) or psychotropic medication
and were admitted as inpatients to the General Clinical Research Center of
Emory University Hospital, Atlanta, Ga, after providing written informed consent.
The study was approved by the Institutional Review Board (Human Investigation
Committee) of Emory University School of Medicine and was conducted from May
1997 to July 1999.

Early Trauma Inventory

The presence or absence of childhood trauma was assessed using the Early
Trauma Inventory (ETI).39 The ETI is a structured
interview that assesses the number, frequency, duration, and subjective impact
of different types of traumatic experiences (physical, sexual, emotional abuse
and general traumas). The ETI scale ranges from 0 to 524 for physical abuse
and from 0 to 1017 for sexual abuse. High test-retest reliability, internal
consistency, and external validity have been reported for the ETI.39 We additionally made an effort to obtain independent
validation of the abuse from court, social service, or medical records and
from family or friends, although not all subjects included in the study were
able to provide such validation. For the diagnosis of depression and other
psychiatric disorders, the Structured Clinical Interview for DSM-IV40 was used.

Cohort Characteristics

There were no significant differences in age, educational status, or
ethnicity among the 4 comparison groups; however, there was a trend for fewer
African Americans in the group of abused women with current major depression
compared with the group of abused women without major depression (Fisher exact
test P = .08). The 4 comparison groups did not differ
with respect to the distribution of women using oral contraceptives (4 of
49) or women withdrawn from therapy with psychotropic medication (11 of 49).
The magnitude of the abuse did not differ between abused women without major
depression (mean ETI sexual abuse score, 131.71; 95% CI, 20.97 to 284.39;
mean ETI physical abuse score, 199.36; 95% CI, 37.07-361.64) and abused women
with major depression (mean ETI sexual abuse score, 70.84; 95% CI, 7.53-140.94;
mean ETI physical abuse score, 173.84; 95% CI, 88.86-258.83).

The mean severity of the depression was in the moderate range for abused
women with major depression (mean Hamilton Depression Rating Scale41 [range, 0-38] score, 19.0; 95% CI, 15.56-22.44) and
nonabused women with major depression (mean Hamilton Depression Rating Scale
score, 21.1; 95% CI, 19.30-22.89). There were no significant differences with
respect to the prevalence of past major depression among women with a history
of childhood abuse without current major depression (8 of 14), women with
a history of childhood abuse with current major depression (9 of 13), and
nonabused women with current major depression (8 of 10). Only 5 of 14 abused
women without current depression met DSM-IV criteria
for PTSD, whereas 11 of 13 abused women with current depression fulfilled
a DSM-IV diagnosis of PTSD (χ21 = 6.68, P = .01).

For the induction of stress, we used a standardized psychosocial stress
protocol that has been shown to reliably induce activation of the hypothalamic-pituitary-adrenal
axis and the autonomic nervous system.42 The
test mainly consists of a 10-minute anticipation and preparation phase and
a subsequent 10-minute public speaking and mental arithmetic task in front
of an audience. In 6 independent validation studies, this protocol was shown
to induce endocrine and autonomic changes reminiscent of stress, which significantly
differ from placebo conditions.42 The magnitude
of endocrine and autonomic responses is generally interpreted as reflecting
biological stress reactivity.42

The psychosocial stress test was performed between 1:30 and 4:00 PM
as described elsewhere.42 Blood samples from
indwelling catheters and heart rate measurements were obtained in 15-minute
intervals before (15 and 0 minutes), during (15 minutes), and after (30, 45,
60, 75, and 90 minutes) the stress exposure. Blood was collected in EDTA tubes,
placed immediately on ice, and centrifuged at 4°C for 10 minutes at 3000
rpm. Plasma was separated, coded, stored at –80°C, and assayed for
ACTH and cortisol concentrations by members of the research team blinded to
group assignment and sample sequence using commercial radioimmunoassays (ACTH:
Nichols, San Juan Capistrano, Calif; cortisol: DiaSorin, Stillwater, Minn).

Data Analysis

Hormone and heart rate data were analyzed using 2-way analysis of covariance
(ANCOVA) with repeated measurement (first factor was group, second repeated
factor was time, and covariate was ethnicity). In the case of significant
effects, between-subjects comparisons were performed for single time points
followed by a priori defined contrasts to compare individual group means.
In addition, maximum levels of hormone concentrations and heart rates were
computed and compared among groups using ANCOVA (factor was group and covariate
was ethnicity) followed by a priori defined contrasts. Homogeneity of variance
was tested using the Levene test.43 In the
case of unequal variance, raw data were logarithm transformed, and all analyses
were repeated. All analyses were 2-tailed, with the level of significance
set at P<.05.

Figure. Pituitary-Adrenal and Autonomic Reactivity
to a Standardized Laboratory Stressor in Women After Childhood Sexual or Physical
Abuse

Mean plasma adrenocorticotropin (ACTH) (A) and cortisol (B) concentrations
and mean heart rates (HR) (C) (± SEMs) before, during (shaded area),
and after psychosocial stress induction in women without a history of significant
early-life stress and no psychiatric disorder (controls, n = 12), women with
a history of childhood sexual or physical abuse without major depression (early-life
stress and no major depression [ELS/non-MDD], n = 14), women with a history
of childhood sexual or physical abuse and current major depression (early-life
stress and major depression [ELS/MDD], n = 13), and women without a history
of significant early-life stress and a current major depression (no early-life
stress and major depression [non-ELS/MDD], n = 10). To convert ACTH from pmol/L
to pg/mL, divide by 0.22. To convert cortisol from nmol/L to mg/dL, divide
by 27.59. Asterisk indicates P<.05 for controls
vs ELS/non-MDD; †, P<.05 for controls vs
ELS/MDD; ‡, P<.05 for ELS/non-MDD vs non-ELS/MDD;
§, P<.01 for controls vs ELS/MDD; ∥, P<.01 for ELS/MDD vs non-ELS/MDD; ¶, P<.01 for ELS/non-MDD vs ELS/MDD; #, P<.05
for ELS/non-MDD vs ELS/MDD; and **, P<.05 for
ELS/MDD vs non-ELS/MDD.

COMMENT

Severe stress early in life is associated with persistent sensitization
of the pituitary-adrenal and autonomic stress response, which, in turn, is
likely related to an increased risk for adulthood psychopathological conditions.
This is the first human study to report persistent changes in stress reactivity
in adult survivors of early trauma. The findings are remarkably consistent
with findings from laboratory animal studies.32,33

Increased pituitary reactivity to stress in some women with a history
of early-life stress without psychiatric disorder may reflect a biological
vulnerability for the development of stress-related psychiatric disorders.
In these women, there appears to exist a counterregulatory adaptation of the
adrenal cortex as reflected by increased ACTH concentrations but normal cortisol
responses, which also has been observed in some animal models of severe early
stress.34,44 The manifestation
of affective or anxiety disorders in adulthood may depend on additive factors,
including genetic vulnerability and recent life stress. These factors, taken
together, may result in relatively high CRF neuronal activity whenever these
women are exposed to stress, ultimately resulting in symptoms of depression
and anxiety.

Depressed subjects without early stress experiences showed normal stress
reactivity, suggesting differential pathophysiology in subtypes of depression.
Increased stress sensitivity may be related to a mixed state of depression
and anxiety, including PTSD symptoms, which develops after early trauma. Recently,
our group has shown that in rats many of the neurobiological consequences
of maternal separation, including CRF hypersecretion, are reversed by treatment
with antidepressants, including paroxetine and reboxetine (P.M. Plotsky, PhD;
C.O. Ladd, BS; R.L. Huot, BS; et al, unpublished data, 2000).

Future studies in survivors of childhood abuse should separate the effects
of different kinds of abuse at different developmental stages and should explore
potential reversibility of this biological stress vulnerability after psychotherapeutic
and psychopharmacological intervention. Such findings may have important implications
for the prevention and treatment of mood and anxiety disorders in survivors
of early trauma. Much effort has recently been directed toward the development
of CRF receptor antagonists for the treatment of depression and anxiety.45 The utility of CRF receptor antagonists in depression
is currently being evaluated in an open-label clinical trial.46
Our findings suggest potential utility of such compounds for the prevention
and treatment of psychopathological conditions related to early-life stress.

Nemeroff CB. The preeminent role of early untoward experience on vulnerability to
major psychiatric disorders: the nature-nurture controversy revisited and
soon to be resolved. Mol Psychiatry.1999;4:106-108.

Figure. Pituitary-Adrenal and Autonomic Reactivity
to a Standardized Laboratory Stressor in Women After Childhood Sexual or Physical
Abuse

Mean plasma adrenocorticotropin (ACTH) (A) and cortisol (B) concentrations
and mean heart rates (HR) (C) (± SEMs) before, during (shaded area),
and after psychosocial stress induction in women without a history of significant
early-life stress and no psychiatric disorder (controls, n = 12), women with
a history of childhood sexual or physical abuse without major depression (early-life
stress and no major depression [ELS/non-MDD], n = 14), women with a history
of childhood sexual or physical abuse and current major depression (early-life
stress and major depression [ELS/MDD], n = 13), and women without a history
of significant early-life stress and a current major depression (no early-life
stress and major depression [non-ELS/MDD], n = 10). To convert ACTH from pmol/L
to pg/mL, divide by 0.22. To convert cortisol from nmol/L to mg/dL, divide
by 27.59. Asterisk indicates P<.05 for controls
vs ELS/non-MDD; †, P<.05 for controls vs
ELS/MDD; ‡, P<.05 for ELS/non-MDD vs non-ELS/MDD;
§, P<.01 for controls vs ELS/MDD; ∥, P<.01 for ELS/MDD vs non-ELS/MDD; ¶, P<.01 for ELS/non-MDD vs ELS/MDD; #, P<.05
for ELS/non-MDD vs ELS/MDD; and **, P<.05 for
ELS/MDD vs non-ELS/MDD.

Nemeroff CB. The preeminent role of early untoward experience on vulnerability to
major psychiatric disorders: the nature-nurture controversy revisited and
soon to be resolved. Mol Psychiatry.1999;4:106-108.

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